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Table 23.6 Commercialized dressings [39]
Product Name Product Type Composition
Manuka guard® medical grade
Manuka honey
Manuka ll
Ectocare Manuka ll
ManukaDress-T
Activon tube
Manuka health Wound gel
Medihoney barrier cream
Medihoney gel Wound & Burn
Dressing
Melladerm plus
Melloxy
MANUKApli
L-Mesitran soft
L-Mesitran ointment
Revamil gel
Revamil balm
SurgihoneyTMRO
Therahoney gel
®
™®
®
®
®
®
®
®
®
®
®
®
®
®
®
Honey 100% Manuka honey
Honey 100% Manuka honey
Honey 100% Manuka honey
Honey 100% Manuka honey
Paste formula 100% Manuka honey
®
Gel formula 94% Manuka honey with natural gelling agents
Cream formula 30% Manuka honey, other non-described components
Gel formula 100% Manuka honey in a hydrocolloidal suspension
Gel formula 45% medical-grade multi-ower honey, other non-
described components
Gel formula 40% medical-grade multi-ower honey, 11% ozonated
vegetable olive oil, other non-described components
Gel formula 100% Manuka honey
Gel formula 40% medical-grade honey (not Manuka) with lanolin,
polyethylene glycol, and vitamins C and E
Gel formula 48% medical-grade honey (not Manuka), lanolin, cod liver
oil, sunower oil, calendula, aloe vera, zinc oxide, and
vitamins C and E
Gel formula 100% medical-grade honey (not Manuka)
Balm formula 25% medical-grade honey (not Manuka), arachis oleum,
cera alba, glyceryl oleate, aqua
Gel formula Mixture of medical-grade honey from various sites/oral
sources engineered to produce hydrogen peroxide and
reactive oxygen species when diluted in water
Gel formula 100% Manuka honey
F. D’Andrea and F. Mosella
size reduction. Established, however, is the superiority of negative pressure on chronic ulcers over
honey-based bandages, as negative pressure
speeds up the formation of granulation tissue.
Therefore, it can be concluded that from a
clinical point of view, honey-based dressings can
be used in the treatment of chronic poorly exuding ulcers only in cases where silver-based products and negative pressure are not available.
23.4.7.2 Burns
The effect of honey on burns is directly related to
its anti-inammatory action. Honey dressings
promote faster healing of rst-degree burns by
reducing inammation, speeding reepithelialization, and reducing the risk of skin
hyperpigmentation. In second-degree burns, on
the other hand, honey-based dressings have not
shown signicantly adequate effects to motivate
their use.
23.4.7.3 Surgical Wounds
Honey-based dressings have shown excellent
results in the treatment of surgical wounds by
accelerating granulation tissue formation, angiogenesis, and re-epithelialization. Reduced risk of
erythema, edema, and infection and better cosmetic results compared with untreated patients
make honey-based products excellent allies in the
treatment of surgical wounds.
23.4.7.4 Ozonids
Ozone is a natural component of the atmosphere
with high oxidizing power characterized by high
reactivity and instability. It is produced in the
stratosphere through the Chapman cycle
(Fig.23.4). Because of its ability to absorb UV
rays produced by the Sun, it prevents the denaturation of proteins allowing life on Earth. On the
other hand, as shown in the 2015 Italian Ministry
of Health pamphlet [48], it can cause irritative
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Fig. 23.4 Chapman
cycle [47]
229
effects to the ocular mucous membranes and the
rst airways, coughing, bronchostrictive phenomena, and altered respiratory function.
Epidemiological studies conducted in urban populations exposed to ozone have shown irritative
symptoms on ocular mucous membranes and the
upper respiratory tract for exposures of several
hours to ozone levels as low as 0.2mg/m3 (hourly
average). In children and young adults, such
symptoms can appear from concentrations as low
as 0.12mg/m3 (hourly average).
Its extreme instability in the gas phase (about
3s) prevented its use until 1854, when the rst
generator was invented.
The rst uses were in industry and for water
purication by exploiting the disinfecting and
sanitizing power. [49].
Ozone has been proposed for the treatment of
numerous diseases (tuberculosis, herniated disks,
dental diseases, HIV, hepatitis, and gangrene).
Since 1984, in accordance with the Madrid
Declaration on Ozone Therapy, intravenous use
of O3 has been prohibited. [50].
The topical route has been used for the treatment of wounds, infections (fungal, bacterial,
and viral), ischemic lesions, and other afictions,
demonstrating efcacy especially in disinfection
and wound healing. It can be used in oily and
gaseous form. [51].
The purpose of ozonated oil is to obtain
ozone-containing formulations with improved
stability to: facilitate its handling; to improve its
storage; to prevent its rapid degradation; to allow
its out-of-hospital treatment; and to reduce the
risk associated with its gaseous form (in high and
inadequate doses).
The observation that O3 tends to bind to the
double bonds of the unsaturated chains of lipids
in plasma provided the basis for the creation of
ozonated oils. Nicola Tesla [52] was the rst to
“load” a vegetable oil with O3 by boiling ozone
for 3 weeks through the oil creating a natural gel
with ozone in suspension: “ozo-oil.” The technology of ozonolysis of highly unsaturated vegetable oils produces oils in which the double bonds
have been saturated by the three oxygen atoms of
ozone; these molecules called “ozonides,”
obtained through a selective catalyzation process
reach a peroxide number around 800 u corresponding to about 220 mg. of O3 per cc.
(Fig.23.5).
Ozonation of oils imparts stability to ‘ozone
and allows its use for the treatment of skin conditions. It has been used empirically as a clinical
therapeutic agent for stulas and post-surgical
wounds, pressure ulcers, and chronic wounds
such as trophic ulcers, ischemic ulcers and diabetic ulcers, psoriasis, and athlete’s foot.
In an aqueous medium such as blood, ozonides are immediately transformed into stable
hydroperoxides. These have the ability to yield
oxygen when the pH increases, for example in
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F. D’Andrea and F. Mosella
–
–
Fig. 23.5 Ozonolysis [53]
– –
– – –
– – –
proton environments that are established in
degenerative and/or ischemic processes, and at
the same time, losing the hydrophobicity characteristic of lipids, they become water-soluble
because they are characterized by a short lipid
chain.
The benecial effects of ozone on wound
healing are likely related to the low molecular
weight and short chain length of fatty acids saturated by ozone and, ultimately, in the “hydrophilicity” of the molecule that allows it to “fuse”
with the cell wall and spill into the cytosol triggering the cycle of reactions related to the transformation of peroxides into alcohols. This
–
–
– – – –
–
reaction combined with the disruption of the
GSH-GSSG molar equilibrium produces a 97.4fold acceleration of the pentose shunt and thus of
glycolysis.
The effects of ozonides are related to [54]:
• reduction of microbial infection,
• debridement effect,
• modulation of the inammatory phase,
• stimulation of angiogenesis,
• biological and enzymatic reactions that promote oxygen metabolism by improving wound
healing.
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231
The study conducted by Cardoso in diabetic
wounds in 2010 showed that the use of topical
ozonides induces an early response with more
cells involved in the repair process, higher angiogenesis than controls, and increased vascular
endothelial growth factors and cyclin D1 expression [55] (Fig.23.6).
Ozonide dressings can be used on acute and
chronic wounds.
Also useful in prevention of pressure sores,
radiation and chemotherapy damage, perilesional
skin changes (xerosis, erythema, itching, desquamation, inammatory states, and alteration of the
skin microbiota).
They are indicated in cases of critical colonization and local infection. In case of infection,
they should be considered supportive of systemic
treatment.
Ozonide-based wound care devices we can
distinguish them into:
simple dressings: spray oils, creams, impregnated gauze, oily preparations in prelled
syringe.
advanced dressings: alginates, hydrogels.
cleansers: rinsing and non-rinsing.
Application methods vary according to the type
of dressing: simple ones, in principle, should be
changed 1–2 times a day (especially application of
cream or oil in skin affections); advanced ones can
be renewed 2–3 times a week, also depending on
the level of exudation and bacterial load.
On application, they may cause a burning/
itching sensation if it relieves in a few minutes.
The oily matrix ensures that they do not adhere
to the wound bed causing microtrauma.
They always require a secondary dressing.
The choice of the latter conditions the timing of
renewal.
They can go under compression bandaging.
Fig. 23.6 Action of ozonides on cellular metabolism
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F. D’Andrea and F. Mosella
23.4.7.5 Mesoglycan
Glycosaminoglycans (GAGs) constitute a class
of complex carbohydrates that interact with a
broad spectrum of proteins involved in numerous
physiological and pathological processes. They
are also known as “mucopolysaccharides”
because of their viscous and lubricating properties. These molecules are present on the surface
of all cells in the extracellular matrix, and some
of them bind to and regulate the activity of
numerous proteins, including chemokines,
growth factors, morphogens, enzymes, and adhesion molecules (Gandhi and Mancera 2008).
Two classes are distinguished:
Non-sulfated, such as hyaluronic acid sulfated,
which include chondroitin sulfate, keratan sulfate,
dermatan sulfate, heparan sulfate, and heparin.
Each individual polysaccharide chain consists
of basic disaccharide units, represented by a hexosamine (glucosamine or galactosamine) and a
uronic acid (glucuronic or hydronic), except for
keratan sulfate in which the uronic acid is
replaced by a hexose (galactose).
GAGs, based on the nature of the hexosamine
residues, are classied into two groups:
Glycosaminoglycans: hyaluronic acid (HA),
keratan sulfate (KS), heparan sulfate (HS), and
heparin; galactosaminoglycans: chondroitin sulfate (CS) and dermatan sulfate (DS).
In nature, all GAG chains, except, HA are
covalently bound to a protein forming proteoglycans (Fig.23.7).
GAGs play important roles in the wound
repair process by regulating: [59]
Fig. 23.7 GAGs are linear negatively charged polysaccharides with molecular weights ranging from 10 to 100kDa
[56]
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• at multiple levels of the assembly of the ECM,
• the activity of proteinases,
• cellular activity through the action of growth
factors, cytokines, and transcription factors,
• the inhibition of proteinases in coagulation/
brinolytic systems.
Mesoglycan since the mid-1980s has been the
subject of scientic attention, especially placed in
correlation with vascular pathology accompanied or
not by thrombotic risk. It belongs to the heparinoid
family. It is composed of a collection of glycosaminoglycans (GAGs) such as heparan sulfate, dermatan sulfate, chondroitin sulfate, and heparin slow.
For years used as an adjuvant in multiple pathologies in which microcirculation alteration plays a key
role (venous ulcers, chronic venous insufciency
(CVI) and Phlebolymphoedema, hemorrhoidal
pathology, and dizziness) [60, 61] (Fig.23.8).
Mesoglycan-based dressing was developed in
Italy in 2014. It consists of mesoglycan (predominantly), alginate, and hyaluronic acid. The mesoglycan contained in the dressing is a natural
preparation of glycosaminoglycans (GAGs)
extracted from the intestinal mucosa of pigs composed of heparan sulfate (HS) (47.5%), dermatan
sulfate (DS) (35.5%), slow-moving heparin
(HEP) (8.5%), and chondroitin sulfate (CS)
(8.5%) [62].
Recent in vitro studies have shown that the
dressing can enhance the processes of reepithelialization and granulation by acting on
epidermal keratinocytes and human dermal
broblasts.
Belvedere et al. demonstrated that mesoglycan can induce strong cytoskeletal reorganization
to increase cell migration and invasion, two key
processes underlying wound healing reepithelialization and granulation [62, 63]. It was
also documented with an immunouorescence
assay that mesoglycan-treated broblasts showed
an increase in broblast-activated protein
(FAP)-α and a remarkable change in shape and
orientation, two common features of reactive
stromal broblasts [64].
Topical use of GAGs is also able to positively
inuence angiogenesis by increasing the formation of new blood vessels invitro. The identied
mechanism includes the induction of endothelialmesenchymal transition, through which endothelial cells acquire a broblast-like phenotype and
become able to migrate, invade, and form new
capillary structures. Finally, the mesoglycan dressing is able to regulate inammatory responses that
are necessary in the early stages of wound repair
but can result in damage due to the recruitment of
dermal, epidermal, and endothelial cells [65].
The dressing is presented as an opaque, conformable, biodegradable matrix.
At marketing, the indication was limited to the
treatment of vascular-type ulcers. Currently, it
has been extended to acute and chronic cleansed
lesions preferably with mild to medium exudation [64].
Fig. 23.8 Disaccharide units [57, 58]
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F. D’Andrea and F. Mosella
Placed on the wound, it forms a gel that has a
barrier effect against bacteria, exerts a buffering
effect on the pH of the wound, maintains a moist
microenvironment, and promotes effective
wound healing.
It requires secondary dressing.
It can be used under compression bandaging.
The timing of dressing changes is unchanged
from the normally adopted protocol.
23.4.7.6 DNA andRibosomes
PDRN (polydeoxyribonucleotide) is a drug
devised in the endowed with marked antiinammatory, tissue repair, and anti-ischemic
activities. These characteristics have aroused
great interest highlighting the multiple elds of
application: orthopedics, ophthalmology, dermatology, wound care, gynecology, ophthalmology,
plastic surgery, immunology, and others.
It is a mixture of deoxyribonucleotides with
molecular weights between 50 and 1500 KDa
(the most represented p.m. is 80-200KDa) and a
chain length between 50 and 2000 base pairs,
derived from the sperm of Oncorhynchus mykiss
(salmon trout) or Oncorhynchus keta (chum
salmon) [66] The compound is extracted and
puried at high temperature through a procedure
that yields a 95% pure active ingredient without
the risk of proteins and peptides causing immune
reactions. The chemical structure of PDRN consists of a low pm weight DNA moiety composed
of a linear polymer of deoxyribonucleotides with
phosphodiester bonds [67]. in which the monomeric units are represented by purine and pyrimidine nucleotides. These polymer chains are
coupled to form a double helix. The monomeric
unit is the nucleotide.
PDRN is likely to be cleaved by active cell
membrane enzymes, providing a source of
purines and pyrimidines to different tissues [68].
Nucleotides and nucleosides have shown a
synergistic effect with several growth factors and
may inuence their production [2]. At therapeutic
concentrations, PDRN has been shown to
increase the growth rate of numerous cells such
as broblasts, chondrocytes, preadipocytes, and
osteoblasts in primary cultures.
The binding of PDNR to the A2A adenosine
receptor plays a key role in:
resolving acute inammation,
stimulating VEGF secretion,
promoting neoangiogenesis,
supporting granulation tissue formation.
Thellung and Sini’s studies conducted in 1999
were instrumental in understanding its mechanism of action. Thellung in his experiment compared the effects of adenosine and PDRN in
primary cultures of human broblasts and showed
that both induced cell growth and that the effects
were abolished by concomitant incubation with
3,7-dimethyl-1-propargylxanthine (DMPX), an
adenosine A2 receptor antagonist [69]. Sini, on
the other hand, placed broblasts in culture in the
presence of PDRN and radioactive amino acids
and demonstrated how cell growth is accompanied by the internalization of PDRN-derived
nucleotides and how these are used in the
“Salvage Pathway,” which represents a kind of
base and nucleoside salvage pathway for DNA
and RNA synthesis in damaged or hypoxic tissues (Figs.23.9 and 23.10).
PDRN is a drug that can be administered
intramuscularly, by local inltration and topical
use. Often the treatment modality involves
embricking between the different modes of
administration. Squadrito’s 2014 study of the
diabetic foot, for example, called for PDRN to be
administered im daily by the intramuscular route
for 5 days/week and by the perilesional route
2days/week for 8weeks [71].
From the literature review and data sheets, we
can infer that PDRN is on the market both in vials
for IM and/or perilesional administration and in
topical preparation.
It is indicated for use on cleansed wounds,
acute and chronic, in the absence of necrotic tissue, that present a blockage of the reparative process. Published clinical studies address the
treatment of diabetic foot injuries, decubitus injuries, grade I-II burns, and injuries with ischemic
character (always after adequate systemic therapies). Useful in the management of a graft har-
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Fig. 23.9 PDRN
mechanisms of action
(modied): interaction
with adenosine A2A
receptor; “Salvage
Pathway” [70]
235
Fig. 23.10 PDRN and reactivation of the reparative process [67]
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F. D’Andrea and F. Mosella
vest site and to improve the survival of skin aps
[72–74].
Formulations for topical use are available in
prelled syringes and as creams.
Some formulations are enriched with hyaluronic
acid to promote granulation tissue formation.
In the case of ulcerated skin lesions, secondary dressing is required. Products can be used
under compression bandaging.
The treatment scheme is diversied:
creams: local application once or twice a day.
syringe preparation: one application to the
wound bed with variable dressing renewal timing, on average every 3–6days.
23.4.7.7 Rigenase
®
Rigenase® is a patent-protected aqueous extract
of Triticum Vulgare, obtained by taking care of
the entire production through a continuous process from the seeds to the nished product. The
total control of the processing allows obtaining
an extract characterized by a high concentration
of the pharmacologically active fraction. It is a
bioinducer: it exerts anti-inammatory, antioxidant action and stimulates broblast and keratinocyte proliferation [75].
Antiphlogistic activity [76, 77] is demonstrated by signicant reduction in the in vitro
expression of some pro-inammatory mediators
(IL-6, PGE2, TNF α) [10, 11] and modulation of
MMP-9 synthesis in the inammatory phase.
Antioxidant function [78] is supported by a
reduction in ROS (NO) levels. This activity was
found to be comparable to that of ascorbic acid.
Fibroblast proliferation [79] is induced by
stimulation to bronectin synthesis, hyaluronic
acid synthetase 2 (HAS2), and actin polymerization while that of keratinocytes [80] is determined by the ability to modulate the expression
of MMP-2 and MMP9 [8].
[81, 82] They require a secondary dressing. We
can schematically divide them into:
simple dressings: impregnated gauze, cream,
spray,
advanced dressings: hydrogels.
Simple dressings may or may not be admixed
with polyhexanide. The combination with polyhexanide confers a reduction in the risk of bacterial contamination and can help in critical
colonization phases. The hydrogel, consisting of
Rigenase®, hydroxyethylcellulose, and polyhexanide, is a useful aid in the wound debridement phase, best in cavity wounds. Bacterial load
control can be further supported by the acidic pH
of the product in spray and hydrogel form.
They always require a secondary dressing that
can be traditional or interactive. Traditional
dressing methods require at least one daily dressing change (cream: 2 applications/day; spray:
2–3 applications/day).
Further broader studies need to be conducted
to conrm the data so far available in the
literature.
23.4.7.9 MMPs Inhibitors
In the reparative process, proteases play an important role both in the physiological process of tissue
repair and in the perpetuation of an inammatory
state that leads to injury chronication.
Metalloproteases (MMPs) are a family of
more than 20 structurally related endopeptidases
involved in physiological processes such as cell
signaling, cell migration, angiogenesis, and degradation of extracellular matrix (ECM) proteins
[83]. So far, 23 have been described. Based on
their substrate specicity, primary structures, and
cellular localization, MMPs are divided into six
classes:
23.4.7.8 Dressings
In general, dressings with Rigenase® should be
used on acute and chronic, cleansed, low- to
medium-exudation wounds. There are some studies that also highlight use in grade I and II burns.
• Collagenases (MMP-1, MMP-8, and
MMP-13).
• Gelatinases (MMP-2 and -9).
• Stromelysins (MMP-3, MMP-10 and
MMP-11).
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• Matrilisins (MMP-7 and MMP-26).
• Membrane-type MMPs (MMP-14, MMP-15,
MMP-16, MMP-17, MMP-24, and
MMP-25).
• Others (MMP-12, MMP-19, MMP-20, MMP21, MMP-23, MMP-27, and MMP-28) [84].
All MMPs, although acting on different sub-
strates, have high similarity in the catalytic
domain and contain the Zn2+ ion. MMP-1,
MMP-2, MMP-8, and MMP-9 have been the subject of careful study for many years in wound
care [85]. Physiologically, they are produced as
proenzymes by tissue cells that contribute to
healing (neutrophils, broblasts, endothelial
cells, and epithelial cells) and by immune cells
recruited in the context of the inammatory process or in response to infection.
In the remodeling of the ECM, human neutro-
phil elastase (NHE) plays an equally important
role, which, in addition to intervening in matrix
degradation, acts on mediators of inammation
[86, 87].
The activity of MMPs is nely regulated
through 4 mechanisms:
• gene expression,
• compartmentalization,
• proenzyme activation,
• inhibition of proteolysis [88],
Proteases are synthesized in an inactive form
(pro-MMPs) subsequently activated by the action
of other MMPs and/or by serine proteases such as
HNE (Fig.23.11).
Tissue inhibitors of metalloproteases (TIMPs)
are molecules produced by numerous cells (mesenchymal, epithelial, and immune system) capable of inhibiting the activity of MMPs by forming
noncovalent bonds with them. They express their
Fig. 23.11 MMP Regulation. [89]
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